Microtubule-interfering agents activate c-Jun N-terminal kinase/stress-activated protein kinase through both Ras and apoptosis signal-regulating kinase pathways.
The essential cellular functions associated with microtubules have led to a wide use of microtubule-interfering agents in cancer chemotherapy with promising results. Although the most well studied action of microtubule-interfering agents is an arrest of cells at the G2/M phase of the cell cycle, other effects may also exist. We have observed that paclitaxel (Taxol), docetaxel (Taxotere), vinblastine, vincristine, nocodazole, and colchicine activate the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) signaling pathway in a variety of human cells. Activation of JNK/SAPK by microtubule-interfering agents is dose-dependent and time-dependent and requires interactions with microtubules. Functional activation of the JNKK/SEK1-JNK/SAPK-c-Jun cascade (where JNKK/SEK1 is JNK kinase/SAPK kinase) was demonstrated by activation of a 12-O-tetradecanoylphorbol-13-acetate response element (TRE) reporter construct in a c-Jun dependent fashion. Microtubule-interfering agents also activated both Ras and apoptosis signal-regulating kinase (ASK1) and coexpression of dominant negative Ras and dominant negative apoptosis signal-regulating kinase exerted individual and additive inhibition of JNK/SAPK activation by microtubule-interfering agents. These findings suggest that multiple signal transduction pathways are involved with cellular detection of microtubular disarray and subsequent activation of JNK/SAPK.
Wang
T H
TH
Department of Obstetrics and Gynecology, Graduate School of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee 37920, USA.
Wang
H S
HS
Ichijo
H
H
Giannakakou
P
P
Foster
J S
JS
Fojo
T
T
Wimalasena
J
J
D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D003078:Colchicine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D008870:Microtubules / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases; D008954:Models, Biological; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014748:Vinca Alkaloids / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism*
D016755:Proto-Oncogene Proteins c-jun; D014748:Vinca Alkaloids; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D018631:ras Proteins; D017239:Paclitaxel; D015739:Nocodazole; D003078:Colchicine